Purinergic receptors can be classified into the P.sub.1 (adenosine) receptors and the P.sub.2 (adenosine 5' triphosphate) receptors. Adenosine receptors can further be delineated into major subclasses, the A.sub.1, A.sub.2 (A.sub.2a and A.sub.2b) and A.sub.3 adenosine receptors. These subtypes are differentiated by molecular structure, radioligand binding profiles, and by pharmacological activity and signal transduction mechanisms. Binding of adenosine, a naturally occurring nucleoside, to specific adenosine receptors leads to either stimulation (A.sub.2 -receptor activation) or inhibition (A.sub.1 -receptor activation) of adenylate cyclase activity resulting in an increase or decrease of intracellular cAMP, respectively. Most tissues and cell types possess either the A.sub.1 or A.sub.2 receptor, or both. Moreover, A.sub.1 adenosine receptors have been identified in the nuclear fraction of splenocytes (Donnabella, Life Sci. 46:1293 (1990)). Specific A.sub.1, A.sub.2, and A.sub.3 adenosine receptor antagonists and agonists are known. See, e.g., Trivedi et al., Structure-Activity Relationships of Adenosine A.sub.1 and A.sub.2 Receptors, In: Adenosine and Adenosine Receptors, M. Williams, Ed., Humana Press, Clifton, N.J., USA (1990); Jacobson et al., J. Medicinal Chem. 35:407 (1992); Fredholm et al., Pharm. Rev. 46:143 (1994); Jacobson, Abstracts from Purines '96, Drug Dev. Res., March 1996, page 112. Divalent ions (Mg.sup.2+ and Ca.sup.2 +) and allosteric enhancers enhance the binding of A.sub.1 adenosine receptor agonists to A.sub.1 adenosine receptors (Kollias-Baker, Circ. Res. 75:961 (1994)). Allosteric enhancers enhance A.sub.1 receptor mediated responses and are described in Bhattacharya, Biochim. Biophys. Acta 1265:15 (1995).
Based on potency profiles of structural analogues for ATP, ATP-sensitive (P2) purinoceptors have been subclassified into P.sub.2X and P.sub.2Y purinoceptors. With few exceptions, P.sub.2X receptors are located on vascular smooth muscle cells and mediate vasoconstriction and P.sub.2Y receptors are located on endothelial cells and mediate vasodilation. Burmstock and Kennedy, Gen. Pharmacol. 16:433 (1985; Ralevic eta 1., Br. J. Phannacol. 103:1108 (1991). P.sub.2X receptors are present on arteries of a number of different species. Bo and Burnstock, J Vas Res 30:87 (1993). The presence of P.sub.2X purinoceptors on pulmonary arteries is reported in Neely, C. F., Am J Physiol 270:L889-L897, 1996.
Inflammatory cells, including monocytes and alveolar macrophages express the A.sub.1, A.sub.2 and A.sub.3 adenosine receptor subtypes. Eppell et al., J. Immunology 143:4141 (1989); Lapin and Whaley, Clin. Exp. Immnunol. 57:454 (1984); Saijadi, et al., J. Immunol. 156:3435 (1996). The presence of A.sub.1 adenosine receptors on human monocytes/macrophages is reported, e.g., in Salmon, J. E., J Immunology 151:2775-2785, 1993. Mature monocytes enter the circulatory system from the bone marrow; some monocytes enter tissues and develop into macrophages in the spleen, lymph nodes, liver, lung, thymus, peritoneum, nervous system, skin and other tissues. Monocytes and macrophages can be identified by morphology, cell surface antigens, and the presence of characteristic enzymes. Both monocytes and macrophages play a role in inflammatory responses and secrete various proteins active in immune and inflammatory responses, including Tumor Necrosis Factor (TNF) and Interleukin I (IL-1)). Upon stimulation, monocytes and macrophages can generate various oxygen metabolites, including superoxide anion and H.sub.2 O.sub.2 that are toxic to both pathogens and normal cells.
Fibroblasts are the major cell type responsible for the synthesis of collagen, a fibrous protein essential for maintaining the integrity of the extracellular matrix found in the dermis of the skin and other connective tissues. The production of collagen is a finely regulated process, and its disturbance may lead to the development of tissue fibrosis. The formation of fibrous tissue is part of the normal healing process after injury, including injury due to surgery. However, in some circumstances there is an abnormal accumulation of fibrous material such that it interferes with the normal function of the affected tissue.
Scar tissue serves only a structural role, but does not contribute to the function of the organ in which it appears. For example, as fibrotic scar tissue replaces heart muscle damaged by hypertension, the heart becomes less elastic and thus less able to do its job. Similarly, pulmonary fibrosis causes the lungs to stiffen and impairs lung function. Fibrotic growth can proliferate and invade healthy surrounding tissue, even after the original injury heals. In most cases fibrosis is a reactive process, and several different factors can apparently modulate the pathways leading to tissue fibrosis. Such factors include the early inflammatory responses, local increase in fibroblast cell populations, modulation of the synthetic function of fibroblasts, and altered regulation of the biosynthesis and degradation of collagen.
Stimulation of fibroblast activity is involved in the development of fibrotic conditions, including spontaneous and induced conditions. Abnormal accumulation of collagen in the extracellular matrix, resulting from excessive fibroblast proliferation and/or collagen production, can cause fibrosis of a number of tissues including the skin. Many common debilitating diseases, such as liver cirrhosis and pulmonary fibrosis, involve the proliferation of fibrous tissue as do certain skin diseases such as scleroderma, and the formation of adhesions, keloids, and hypertrophic scars.